Novel thienobenzazepines as anti-depressants

ABSTRACT

Novel 4-(alkylaminoalkyl)-(4H)-thieno-(3,2-b)(f)-benzazepines of the formula WHEREIN R1 and R2 are selected from the group consisting of hydrogen, halogen, -CF3, lower alkoxy optionally substituted, lower alkylthio, lower alkyl, optionally substituted sulfonamido, diloweralkylamino and acylamino wherein the acyl is derived from an organic carboxylic acid of one to 18 carbon atoms, R is selected from the group consisting of hydrogen and lower alkyl, A is alkylene of two to five carbon atoms, optionally substituted by lower alkyl, B is selected from the group consisting of hydrogen, lower alkyl and arloweralkyl, C is selected from the group consisting of lower alkyl and arloweralkyl and B and C taken together are alkylene of two to six carbon atoms optionally interrupted with one or two heteroatoms, Y is selected from the group consisting of hydrogen, hydroxy, lower alkoxy and lower alkanoyloxy, X is hydrogen and taken together with Y forms a carbon-carbon double bond, Z&#39;&#39; is selected from the group consisting of hydrogen and lower alkyl and Z is selected from the group consisting of hydrogen, lower alkyl and lower alkoxy and taken with Y forms a member of the group consisting of 0, lower alkylenedioxy, loweralkylenedithio and thioloweralkyleneoxy and their non-toxic, pharmaceutically acceptable acid addition salts having antidepressant activity with a large therapeutic index and their preparation and novel intermediates.

nited States Patent [191 Nedelec et al.

[451 Dec. 24, 1974 NOVEL THIENOBENZAZEPINES AS ANTll-DEPRESSANTS [75] Inventors: Lucien Nedelec, Le Raincy; Jacques Guillaume, Aulnay-sous-Bois; Andre Allais, Les Lilas, all of France [73] Assignee: Roussel-Uclaf, Paris, France [22] Filed: Oct. 24, 1973 [21] Appl. No.: 409,144

Related U.S. Application Data [62] Division of Ser. No. 230,124, Feb. 28, 1972, Pat, No.

[30] Foreign Application Priority Data Mar. l, 1971 France 71.06917 [52] U.S. Cl. 424/275 [51] lint. Cl A61k 27/00 [58] Field of Search 424/244, 275

Primary Examiner-Stanley J. Friedman Attorney, Agent, or FirmHammond & Littell [57] ABSTRACT Novel 4-( alkylaminoalkyl )-[4l-l]-thieno-[ 3 ,2-b] [f] benzazepines of the formula wherein R and R are selected from the group consisting of hydrogen, halogen, CF lower alkoxy optionally substituted, lower alkylthio, lower alkyl, op-

tionally substituted sulfonamido, diloweralkylamino and acylamino wherein the acyl is derived from an organic carboxylic acid of l to 18 carbon atoms, R is selected from the group consisting of hydrogen and lower alkyl, A is alkylene of 2 to 5 carbon atoms, optionally substituted by lower alkyl, 8 is selected from the group consisting of hydrogen, lower alkyl and arloweralkyl, C is selected from the group consisting of lower alkyl and arloweralkyl and B and C taken together are alkylene of 2 to 6 carbon atoms optionally interrupted with l or 2 heteroatoms, Y is selected from the group consisting of hydrogen, hydroxy, lower alkoxy and lower alkanoyloxy, X is hydrogen and taken together with Y forms a carbon-carbon double bond, Z is selected from the group consisting of hydrogen and lower alkyl and Z is selected from the group consisting of hydrogen, lower alkyl and lower alkoxy and taken with Y forms a member of the group consisting of =0, lower alkylenedioxy, loweralkylenedithio and thioloweralkyleneoxy and their nontoxic, pharmaceutically acceptable acid addition salts having antidepressant activity with a large therapeutic index and their preparation and novel intermediates.

11 Claims, No Drawings NOVEL THIENOBENZAZEPINES AS ANTI-DEPRESSANTS PRIOR APPLICATION This application is a division of copending commonly assigned U.S. Pat. application Ser. No. 230,124 filed Feb. 28, 1972, now U.S. Pat. No. 3,787,445.

OEJECTS OF THE INVENTION It is an object of the invention to provide the novel thienobenzazepines of formula I.

It is a further object of the invention to provide novel process for the preparation of the thienobenzazepines of formula I.

It is another object of the invention to provide novel antidepressant compositions.

It is an additional object of the invention to provide a novel method of alleviating depression in warmblQQded animal These and other objects and advantages of the invention will become obvious from the following detail description.

THE INVENTION The novel thienobenzazepines of the invention are selected from the group consisting of compounds of the formula R 2 Z? z s l l la X/ N B l N .A" \C wherein R and R are selected from the group consisting of hydrogen, halogen CF lower alkoxy optionally substituted, lower alkylthio, lower alkyl, optionally substituted sulfonamido, diloweralkylamino and acylamino wherein the acyl is derived from an organic carboxylic acid of one to 18 carbon atoms, R is selected from the group consisting of hydrogen and lower alkyl, A is alkylene of two to five carbon atoms optionally substituted by lower alkyl, B is selected from the group consisting of hydrogen, lower alkyl and arloweralkyl, C is selected from the group consisting of lower alkyl and arloweralkyl and B and C taken together are alkylene of two to six carbon atoms optionally interrupted with one or two heteroatoms, Y is selected from the group consisting of hydrogen, hydroxy, lower alkoxy and lower alkanoyloxy, X is hydrogen and taken together with Y forms a carbon-carbon double bond, Z is selected from the group consisting of hydrogen and lower alkyl and Z is selected from the group consisting of hydrogen, lower alkyl and lower alkoxy and taken with Y forms a member of the group consisting of =0, lower alkylenedioxy, lower alkylenedithio and thioloweralkyleneoxy and their non-toxic, pharmaceutically acceptable acid addition salts.

Examples of suitable acids for the formation of the acid addition salts are mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid and organic acids such as maleic acid, fumaric acid, acetic acid, tartaric acid, etc.

Examples of the specific compounds of formula I are 4-(y-dimethylaminopropyl)-[4H]- thieno-[3,2-b] [j]- benzazepine and its acid fumarate, 4-(ymethylaminopropyl)-9,l0-dihydro-[4H1-thieno-l3,2- b] [f]-benzazepine and its hydrochloride, 4-(ydimethylaminopropyl)-9,l0-dihydro-[4Hl-thieno-[3,2- b] [fl-benzazepine and its hydrochloride, 4-(7- dimethylaminopropyU-l0-hydroxy-9,10-dihydro- [4H]-thieno-[3,2-b] [f]-benezazepine and its acid fumarate, lO-oxo-4-(y-dimethylaminopropyl )-9, l 0- dihydro-[4H1-thieno [3,2-b] [f]-benzazepine and its acid fumarate and 4-(y-dimethylamino-B-methylpropyl)-9,l0-dihydro-[4H]-thieno-[3.2-b] [f]- benzazepine and its hydrochloride.

The novel process of the invention for the preparation of compounds of the formula wherein R, R R A, B and C have the above definitions and Z is hydrogen comprises reacting a 10 hydroxy-9,l0-dihydro-[4Hl-thienobenzazepine of the formula with an acid agent to obtain the corresponding [4H]- thieno-[3,2-b] [f]-benzazepine of formula II which may be salified by addition of a mineral or organic acid or dealkylated by reaction with lower alkyl halofo rmate followed by alkaline hydrolysis. The acid agent may be a mineral acid such as sulfuric acid, perchloric acid or hydrochloric acid or on organic acid such as methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid.

The l0-hydroxy-9,lO-dihydro-[4H1- thienobenzazepine of formula III may be prepared according to the invention by reacting a l0-oxothienobenzazepine of the formula wherein R, R R A, B and C have the above definitions with a reducing agent to form the corresponding l0-hydroxy-9,l0-dihydro-[4H]-thienobenzazepine of formula III which may be salified with a mineral or or wherein R, R and R have the above definitions and Y and Z are selected from the group consisting of lower alkoxy and lower alkylthio or taken together are selected from the group consisting of lower alkylenedioxy, lower alkylenedithio and thioloweralkyleneoxy with an alkylaminoalkyl halide of the formula wherein A, B and C have the above definitions and Hal is selected from the group consisting of chlorine, bromine and iodine in the presence of a basic agent to form the compound of the formula R 1 Y Z R R1 /\IlI/ and reacting the latter with an acid hydrolysis agent to form the corresponding compound of formula IV which may be salified with a mineral or organic acid or dealkylated with alkyl haloformate followed by alkaline hydrolysis.

Preferably, the basic agent is an alkali metal hydride, amide or alcoholate or a metallation agent such as dimethyl sodium or diphenyl sodium and the acid hydrolysis agent is an aqueous mineral or organic acid, a ketonic acid or aldehydic acid. Particularly preferred as mineral acids are hydrochloric acid, sulfuric acid or perchloric acid and as organic acids are formic acid, acetic acid, tartaric acid, oxalic acid or citric acid. The ketonic acid may be pyruvic acid or levulinic acid and the aldehydic acid may be glyoxylic acid or malonaldehydric acid.

The novel process of the invention for the preparation of thienobenzazepines of the formula (1 VIII wherein R, R R A, B and C have the above definitions comprises reacting a 9,l0-dihydro-lO-Y,Z- thienobenzazepine of the formula V wherein Y and Z are lower alkoxy or lower alkylthio and taken together form a member of the group consisting of lower alkylenedioxy, loweralkyleneditho and thioloweralkyleneoxy with an acid hydrolysis agent to form a lO-keto compound of the formula and reacting the latter with a strong reducing agent to form the corresponding 9,10-dihydrothienobenzazepine of the formula L i l R and reacting the latter with amino halide of formula VI in the presence of a basic agent to obtain the corresponding benzazepine of formula Vlll which can be salified by addition of a mineral or organic acid or dealkylated by reaction with lower alkyl haloformate and then alkaline hydrolysis.

The acid hydrolysis agent is preferably an aqueous organic or inorganic acid, a ketonic acid or an aldehydic acid and the strong reducing agent is an alkaline metal mixed hydride such as or alkali metal aluminum hydride in the presence of aluminum halide. The reducing agent may also be hydrogen in the presence of a platinum group metal catalyst or a metal such as zinc in the presence of a mineral acid or hydrazine in a basic media. The alkylaminoalkyl halide may be the chloride or bromide and the basic agent is preferably an alkali metal hydride.

Another process of the invention for the preparation of a compound of formula Vlll comprises reacting a l0-oxo-compound of formula IV with a strong reducing agent to form the corresponding compound of formula Vlll which can then be salified or dealkylated. The strong reducing agent may be an alkali metal aluminum hydride in the presence of an aluminum salt or hydrogen in the presence of a platinum group metal catalyst or hydrazine in a basic medium or a metal such as zinc in a mineral acid.

Another process for the preparation of a thienobenzazepines of formula I] comprises reacting a lO-oxocompound of formula [X with a reducing agent to obtain a 9,lO-dihydro compound of the formula wherein Z is hydrogen, dehydrating the latter by heating in the presence of a metallic oxide to form a compound of the formula ve. l R2 N E f XII and alkylating the latter by reaction with an amino alkyl halide of formula VI in the presence of a basic agent to obtain the corresponding compound of formula II.

In the preferred mode of the said process, the reducing agent is an alkali metal borohydride such as sodium, potassium, or lithium borohydride and the dehydration is effected by refluxing in a monocyclic aromatic hydrocarbon such as benzene, toluene, xylene or cymene in the presence of a metallic oxide such alumina.

The compounds of formula I wherein Z and/or 2 are lower alkyl may be prepared by reacting a 10-oxo compound of formula IV with an alkylating agent in the presence of a basic agent to obtain a compound of for mula I wherein z is lower alkyl and Z and Y form which can be reduced to obtain the corresponding hydroxy compound which can be dehydrated to obtain a compound of formula I wherein Z is lower alkyl and X and Y form a double bond and Z is hydrogen which may be subjected to hydrogenolysis to form the corresponding 9,10-dihydro [4H]-thieno-[3,2-b] [f]- benzazepine.

The lO-oxo-compounds of formula IV may also be reacted with an organometallic reactant to form the corresponding l0-lower alkyl carbinol which may be dehydrated to form the corresponding [4H]-thieno- [3,2-b] [fl-benzazepine wherein Z is lower alkyl or subjected to hydrogenolysis to form the corresponding 9,10-dihydro-[4H1-thieno-[3,Z-b] [f]-benzazepine wherein Z is lower alkyl.

The lO-keto compound of formula I wherein Z and Y are =0 and Z is lower alkyl may also be subjected to reaction with an organometallic agent to form the corresponding 10-hydroxy-9,l0-dihydro-[4H1-thieno- [3,2-b] [f]-benzazepine of formula I wherein Z and Z are lower alkyl, dehydrating the latter to form a thieno- [3,2-b] [fl-benzazepine wherein Z and Z are lower alkyl, or subjecting the lO-hydroxy compound to hydrogenolysis to form the corresponding 9,10-dihydrothieno-[3,2-b] [f]-benzazepine wherein Z and Z are lower alkyl.

The novel intermediates of the invention have the formula 6 wherein R, R, and R have the above definitions, X is hydrogen or together with Y forms a carbon-carbon double band, Y is hydrogen or hydroxy and together with Z forms =0 and Z is hydrogen.

The 9,10-dihydro-[4H]-thieno-[3,2-b] [f]- benzazepines of formula V may be prepared as described in copending, commonly assigned US. Pat. application Ser. No. 230,123 filed on even date herewith (attorneys docket No. 146,490) now US. Pat. No. 3,767,676, by reacting an o-nitrophenylacetic acid of the formula I GH2CO OH with a bromothiophene of the formula I Br l s in the presence of a Lewis acid to form a thiophene of the formula reacting the latter with a carbonyl blocking agent and reducing the resulting product to form a compound of the formula wherein A and A are the carbonyl blocking group and cyclizing the latter in the presence of a cuprous salt.

The novel antidepressant compositions of the invention are comprised of an effective amount of at least one compound of formula I or its non-toxic, pharmaceutically acceptable acid addition salts and a pharmaceutical carrier. The usual individual dose is 5 to 50 mg in adults depending upon the specific compound and the therapeutic use. The compositions may be in the form of injectable solutions or suspensions in individual or multiple dose flacons or in the form of tablets, coated tablets, syrups, capsules, emulsions or suppositories.

The compositions of the invention are clearly differentiated from N-alkyl-dihydrodibenzazepines such as imipramine, trimeprimine, desipramine or opipramol by a substantially elevated antidepressant activity with a substantially lower acute toxicity determined intraperitoneally. The average lethal dose for imipramine, for example, is mg/kg with mice while that for the compounds of the invention is -300 mg/kg for mice. This means that the compounds of the invention have a greater therapeutic index and are safer for prolonged administration. The compounds have been found to be active at doses in which the side effects of classic antidepressants are not exhibited.

The novel method of the invention for treating or preventing depression in warm-blooded animals comprises administering to warm-blooded animals an effective antidepressant amount of at least one compound of formula I or its nontoxic, pharmaceutically acceptable acid addition salts. The compounds may be administered orally, reactally or parentally. The usual effective daily dose is 0.2 to 6 mg/kg.

1n the following examples there are described several preferred embodiments to illustrate the invention. However, it should be understood that the invention is to be limited only as defined in the appended claims.

EXAMPLE 1 FUMARATE OF 10-OXO-4-(y- DlMETHYLAMINOPROPYL)-9,l-Dll-lYDRO-[4H] THIENO [3,2-b] [f]-BENZAZEPINE 6.5 g of l0,10-ethylenedioxy-9,lO-dihydro [4H] thieno [3,2-b] [f] benzazepine were dissolved with agitation in 250 ml of xylene and then 1.25 g of 50% sodium hydride in vaseline oil was added. The mixture was refluxed for 25 minutes and after cooling, 12.5 ml of a a-dimethylaminopropyl chloride were added. The mixture was refluxed for 6 hours and after cooling, the reaction mixture was added to ice. The mixture was decanted and the aqueous phase was extracted with ethyl acetate. The organic phases containing the intermediate, l0,l0-ethylenedioxy-4-(y-dimethylaminopropyl)- 9,l0-dihydro-[4H]-thieno [3,2-b] [f]-benzazepine was washed with water and then was extracted with 2N hydrochloric acid. The amine fraction was made alkaline by the addition of sodium hydroxide and was reextracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and distilled to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with a 60-30-10 chloroform-acetone-triethylamine mixture. The eluant was evaporated to obtain 4.72 g of 10-oxo-4-(y-dimethylaminopropyl)-9,10-dihydro-[4H] thieno [3,2-b] [f]-benzazepine.

2 g of the said product were dissolved in 10 ml of methanol and after the addition of a solution of 770 mg of fumaric acid in methanol, the methanol was distilled off while being replaced with ethyl acetate until turbid. After crystallization started, the mixture was iced for 30 minutes and vacuum filtered and the recovered precipitate was washed with ethyl acetate and dried in vacuo to obtain 2.24 g of the fumarate of l0-oxo-4-(ydimethylaminopropyl)-9,10-dihydro [4H] thieno-[3,2- b] [f]-benzazepine melting at 198C. The product occurred in the form of pale yellow crystals soluble in water, methanol and ethanol and slightly soluble in chlorinated organic solvents. For analysis, the product was crystallized from isopropanol and the melting point did not change.

Analysis: C H O N S; molecular weight 416.50 Calculated: c 60.56 an 5.81 %N 6.72 %s 7.70 Found: 60.4 5.7 6.6 7.4

Max. at 247 nm E 269 e 11,200 Max. at 275 nm E 188 e 7.850 lnflex. towards 326 nm E,,,,," lnflex. towards 353 nm E 210 Max. at 358 nm E 216 e 9.000

The l0,l0-ethylenedioxy-4-(ydimethylaminopropyl)-9,l0-dihydro-[4H]-thieno [3,2- b] [fl-benzazepine contained in the organic phase was recovered by drying over magnesium sulfate and evaporation to dryness. The said base was reacted with fumaric acid to obtain the corresponding fumarate in the form of a yellow solid melting at C and soluble in methanol and water and slightly soluble in ethanol and chloroform.

EXAMPLE ll 10-HYDROXY-4-(y-DIMETHYLAMINOPROPYL)- 9,10-DlHYDRO-[4H]-THlENO-[3,2-b] [f]- BENZAZEPINE 500 mg of lithium aluminum hydride were added to a mixture of 5 g of l0-oxo-4-(a-dimethylaminopropyl)- 9,l0-dihydro-[4H]-thieno-[3,2-b] [f]-benzazepine in 200 ml of tetrahydrofuran and the mixture was stirred at room temperature for 4 hours and then was cooled. The mixture was added to ethyl acetate and filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with a 6-3-1 chloroformacetonetriethylamine mixture and the eluant was evaporated to obtain 4.12 g of l0-hydroxy-4-( 'ydimethylaminopropyl)-9,l0-dihydro-[4H]-thieno-[3,2- b] [fl-benzazepine in the form of a yellow amorphous product soluble in alcohols and chlorinated organic solvents and insoluble in water. IR Spectrum (chloroform):

Presence of OH at 3570" of aromatic and U.V. S ectrum (ethanol): lnilex. towards 234 nm E 214 Max. at 262-263 nm E 172 e 5200 Max. at 295 nm E 156 e 4.700 Max. at 385 nm E =l The said product can be salified with fumaric acid to form the acid fumarate thereof.

EXAMPLE lll 4-(y-DIMETHYLAM1NOPROPYL)-[4Hl-THlENO- [3,2-b] [f]-BENZAZEPINE AND ITS ACID FUMA- RATE 7 ml of concentrated hydrochloric acid were added with agitation to a solution of 3.5 g of l0-hydroxy-4-(ydimethylaminopropyl)-9,l0-dihydro-[4H]-thieno-[3,2- b]-benzazepine in 70 ml of acetone and the mixture was stirred at room temperature for 30 minutes and was then poured over ice. The mixture was made alkaline by addition of ammonium hydroxide and was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and distilled to dryness under reduced pressure. The residue was dissolved in 30 ml of ether and the solution was filtered and evaporated to dryness under reduced pressure to obtain 2.95 g of 4-(y-dimethylaminopropyl)- [4H]-thieno-[3,2-b] [f]-benzazepine.

2.95 g of the said base were dissolved in 10 ml of methanol and then a solution of 1.15 g of fumaric acid in methanol was added. The mixture was filtered and the methanol was distilled while being replaced with ethyl acetate to the point of turbidity. Crystallization was started and the mixture was iced for 30 minutes and then vacuum filtered. The precipitate was washed with ethyl acetate and dried in vacuo. The residue was dissolved in 20 volumes of refluxing isopropanol, and the solution was filtered and concentrated to half its volume. Crystallization was started and the mixture was iced for one hour and then vacuum filtered. The precipitate was washed and dried in vacuo to obtain 3.2 g of acid fumarate of 4-(y-dimethylaminopropyl)-[4H]- thieno-[3,2-b] [f]-benzazepine melting at 166 C. The product occurred in the form of yellow crystals soluble in methanol and ethanol and slightly soluble in water. Analysis: C l-1 O N S; molecular weight 400.50

Calculated: Found:

%C 62.98 71H 6.04 %N 6.99 "/25 8.01

U.V. Spectrum (ethanol):

4-(y-DlMETl-1YLAMINOPROPYL)-9,IO-DIHYDRO- [4H]-Tl-llENO-[3,2-b] [f]-BENZAZEPINE 4 g of lithium aluminum hydride were added with stirring in portions to a cooled suspension of 4 g of 10- oxo-4-(y-dimethylaminopropyl)-9,10-dihydro-[4l-l1- thieno-[3,2-b] [f]-benzazepine in 160 ml of tetrahydrofuran while keeping the temperature below C and after 4 g of aluminum chloride were added, the mixture was stirred for 2 hours at 0 C. Excess lithium aluminum hydride was destroyed by the addition of isopropanol and 2N sodium hydroxide was added to the mixture which was filtered. The filter was rinsed with water, then methylene chloride and the mixture was decanted. The aqueous phase was extracted with methylene chloride and the organic phases were washed with water, dried over magnesium sulfate and distilled to dryness under reduced pressure to obtain 3.48 of product which was combined with the product from a preceding test beginning with 2 g of the -oxo compound. The mixture was chromatographed over silica gel and eluted with a chloroform-acetone-triethylamine (60-3- 0-10) mixture. Evaporation of the eluant gave 1.62 g of residue which was combined with a chromatographed product from a preceding test beginning with 2 g of the l0-oxo compound. The product was purified by chromatography over silica gel and evaporation of the eluant gives 2.1 g of 4-(y-dimethylaminopropyl)- 9,10-dihydro-[4H]-thieno-3,2-b] [f]-benzazepine in the form of a chestnut liquid soluble in alcohols, ethers and methylene chloride and insoluble in water.

U.V. Spectrum (ethanol):

lnflex. towards 232 nm E 282 -Continued U.V. Spectrum (ethanol): Max. at 268 nm E 203 e 5,800 Max. at 295 nm E 159 e 4,550 lnflex. towards 358 nm E 2 EXAMPLE V 4-(y-D1METHYLAM1NOPROPYL)-9,IO-DIHYDRO- [41-1]-Tl-llENO-[3,2-b]-[f]-BENZAZEPINE STEP A; 10-OXO-9,10-DlHYDRO-[4H1-THIENO- [3,2-b] [f]-BENZAZEP1NE 20 ml of concentrated hydrochloric acid were added to a mixture of 20 g of 10,10-ethylenedioxy-9,10- dihydro-[4l-l]-thieno[3,2-b] [f]-benzazepine and 200 ml of ethanol and the mixture was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure to ml and thee solution was then poured into a water-ice mixture and was extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulfate, treated with activated carbon, filtered and distilled to dryness under reduced pressure. The residue was dissolved in 100 ml of refluxing ethanol, and the solution was filtered and concentrated to 60 ml and filtered. The recovered precipitate was washed with ethanol and dried in vacuo at 70 C to obtain 7.75 g of l0-oxo-9, l0 dihydro-[4H]-thieno-[3,2-b] [f]-benzazepine. Concentration of the mother liquors gave a second crop of 5.35 g for a total yield of 13.10 g (79 of the said product. The product occurred in the form of yellow crystals melting at C and soluble in chlorinated organic solvents and alcohols, slightly soluble in ether and benzene and insoluble in water. Analysis: C, H ONS; molecular weight 215.28

Calculated: 7rC 66.95 7rH 4.21 71N 6.51 715 14.90 Found: 67.2 4.4 6.3 14.6

1R Spectrum (chloroform):

Presence of NH at 3,402 complex carbonyl at 1,643 and 1,636" with a shoulder at 1,611"' with the carbonyl band U.V. Spectrum (ethanol):

Max. at 245 nm E 872 e 18,750 Max. at 275 nm E 330 e 7,100 lnflex towards 322 nm E 133 Max. at 360 nm E 422 e 9,000

STEP B: [4H]-9,l0DlHYDRO-Tl-llENO-[3,2-b] [f]- BENZAZEPINE 7 g of 10-oxo-9,lO-dihydro-[4l-l]-thieno-[3,2-b] [f]- benzazepine were dissolved with stirring in 280 ml of tetrahydrofuran at temperatures below 0 C and then 7 g of lithium aluminum hydride and then 7 g of aluminum chloride were added thereto. The mixture was Max. at 304 nm droxide. The mixture was filtered and the filtrate was extracted with methylene chloride. The organic phases were washed with an aqueous sodium chloride solution, dried over magnesium sulfate and distilled to dryness under reduced pressure to obtain 7 g of product. The residue was subjected to chromatography over silica gel and eluted with a 60-3040 mixture of cyclohexane-chloroform-triethylamine. The solution was distilled to dryness and the residue was dissolved in 10 volumes of ether. The solution was filtered, treated with carbon black and concentrated by heating to the point of crystallization. 10 volumes of pentane were added and the mixture was vacuum filtered. The precipitate was washed with pentane and dried under reduced pressure to obtain 9,10-dihydro-[4H]-thieno-[3,2-b] [f]- benzazepine melting at 1 14 C. For analysis, the product was crystallized from isopropyl ether without change of the melting point. The product occurred in the form of beige crystals soluble in chlorinated organic solvents, alcohols, benzene and ether and insoluble in water.

Analysis: C H NS; molecular weight 201.29

Calculated: %C 71.61 %H 5.51 7(N 6.96 %5 15.93 Found: 71.4 5.6 7.0155

IR Spectrum (chloroform):

Presence of NH at 3,4l6"" and of aromatic and absence of carbonyl U.V. Spectrum (ethanol):

Max. at 229-230 nm 6 =12 800 Max. at 265 nm 5 8,060 e 8,200

STEP C: 4-(y-DIMETHYLAMINOPROPYL)-9,l0- DlHYDRO-[4H]-TH1ENO-[3,2-b] [f]- BENZAZEPINE 4 g of 9,10-dihydro-[4H]-thieno-[3,2-b] [f]- benzazepine were dissolved with stirring in 80 ml of xylene and after the addition of 1.15 g of 50% sodium hydride in vaseline oil, the mixture was refluxed for 30 minutes and then cooled to 50 C. 8 ml of 'y-dimethylaminopropyl chloride were added and the mixture was refluxed for 5 hours and then cooled. The mixture was poured over ice-water and was then extracted with ether. The ether phase was washed with water and then was extracted with 2N hydrochloric acid. The acid extract was made alkaline by the addition of sodium hydroxide and the aqueous phase was extracted with ether. The ether phase was washed with water, dried over magnesium sulfate and distilled to dryness under reduced pressure to obtain 5.7 g of 4-(ydimethylaminopropyl)-9,l-dihydro-[4H1-thieno-[3,2- b] [f]-benzazepine identical to the product of Example 1V.

EXAMPLE V1 HYDROCHLORIDE OF 4-(y- METHYLAMlNOPROPYL)-9,10-DIHYDRO-[4H1- THlENO-[3,2-b] [fl-BENZAZEPINE 5.7 g of 4-(y-dirnethylaminopropyl)-9,IO-dihydro- [4H]-thieno-[3,2-b] [fl-benzazepine were dissolved with stirring in 57 ml of benzene and after the addition of 8.5 ml of ethyl chloroformate, the mixture was refluxed for hours. After cooling, the mixture was poured over ice and was extracted with ethyl acetate.

The organic phase was washed with 2N hydrochloric acid, then with water, dried over magnesium sulfate and distilled to dryness under reduced pressure to obtain 6.73 g of 4-(y-N-methyl-N- ethoxycarbonylaminopropyl)-9,10-dihydro-[4Hlthieno-[3,2-b] [f]-benzazepine.

The latter product was dissolved with stirring in 67 ml of n-butanol and after the addition of 6.73 g of potassium hydroxide pellets, the mixture was refluxed for 20 hours. Water was then added thereto and the mixture was extracted with ether. The organic phase was extracted with 2N hydrochloric acid and the acid aqueous phase was made alkaline by addition of sodium hydroxide. The aqueous phase was extracted with ether and the ether phase was washed with water, dried over magnesium sulfate and distilled to dryness under reduced pressure to obtain 4.25 g (79% yield) of 4-(ymethylaminopropyl)-9,l0-dihydro-[4H]-thieno-[3,2- b] [f]-benzazepine.

4.25 g of the latter product were dissolved in 30 ml of isopropanol and a saturated solution of hydrochloric acid in ethyl acetate was added until the pH was just acid. The ethyl acetate was distilled off and the mixture was filtered. The filtrate was concentrated to 20 ml and crystallization was induced. After standing for 30 minutes, the mixture was vacuum filtered and the precipitate was washed with isopropanol and dried in vacuo to obtain 3.95 g of the hydrochloride of 4-(ymethylaminopropyl)-9,10-dihydro-[4H]-thieno-[3,2- b] [f]-benzazepine melting at 217 C.

For analysis, the product was crystallized from isopropanol without changing the melting point. The product occurred in the form of beige crystals soluble in water, ethanol, methanol and chloroform.

Analysis: C H N SCl; molecular weight 308.88 Calculated: 71c 62.22 71H 6.85 VIN 9.07 /(s10.3s /(C1 11.48 Found: 61.9 6.8 8.9 10.2 11.7

U.V. Spectrum (ethanol):

lnflex. towards 231 nm E 264 Max. at 266 nm E 188 c 5,800 Max. at 291 nm E 144 e 4,450

IR Spectrum (chloroform):

Presence of aromatic and strong absorption between 3,625 and 3,875"'"' and between 2.367 and 2.500 RMN Spectrum (CDCl aromatic protons of thiophene ring 407.5 413-4155 and 421 Hz aromatic protons of benzene ring 420 to 440 Hz protons of dihydroazepine ring at 184 Hz alkylene chain a 224 231-237 Hz B: 117- 125- 132- 139Hz 7: 167-175 184 Hz methyl of nitrogen at 147 Hz EXAMPLE Vll HYDROCHLORIDE OF 4-(y-DlMETHYLAM1NO-B- METHYLPROPYL)-9,l0-DlHYDRO-[4H1-TH1ENO- [3,2-b] [fl-BENZAZEPINE 3.5 g of 9,10-dihydro [4H]-thieno-[3,2-bl [f]- benzazepine were dissolved with stirring in ml of xylene and after the addition of l g of 50% sodium hydride suspension in vaseline oil, the mixture was refluxed for 30 minutes and then was slightly cooled. 7 ml of 1-dimethylamino-2-methy1-3-chloropropane [Bourquin, Helv, Vol. 41 (1958), p. 1,072] were added thereto and the mixture was refluxed for 2 hours and then cooled. The mixture was poured into a water-ice mixture and was then extracted with ether. The ether phase was washed with water and extracted with 2N hydrochloric acid. The acid aqueous phase was made alkaline by the addition of sodium hydroxide and was reextracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, treated with activated carbon, filtered and distilled to dryness in vacuo to obtain 5.5 g of 4-(7- dimethylamino-B-methylpropyl)-9,10-dihydro-[4H1- thieno-[3,2-b] [f]-benzazepine.

The 5.5 g of said product were dissolved in 50 ml of ethyl acetate and then a solution of hydrochloric acid in ethyl acetate was added slowly until the pH was 4. The mixture was heated to reflux and crystallization was induced. After standing for 30 minutes, the mixture was vacuum filtered and the precipitate was washed with ethyl acetate and dried in vacuo at 70 C. After crystallization from isopropanol, there were obtained 4.95 g of hydrochloride of 4-(y-dimethylamino- B-methyl-propyl)-9,l-dihydro-[4H]-thieno-[3,2-b] [f]-benzazepine melting at 210 C. The product occurred in the form of beige crystals soluble in water, chloroform and ethanol.

Analysis: C H N SCl; molecular weight 336.94 Calculated: %c 64.17 %H 7.48 %N 8.31%5 9.52 %c1 10.52 Found: 64.0 7.5 8.2 9.3 10.8

U.V. Spectrum (ethanol):

lnflex. towards 235 nm E 230 Max. at 267 nm E 171 e 5,750 Max. at 293 nm E 131 E 4,400

The starting 1-dimethylamino-2-methyl-3- chloropropane was prepared by dissolving 50 g of the hydrochloride of l-dimethy1amino-2-methyl-3- chloropropane in 50 ml of water cooled in an ice bath, adding 50 ml of sodium hydroxide, extracting the latter with ether, washing the ether phase with water, drying over magnesium sulfate, evaporating the ether and rectifying the residue under reduced pressure to obtain 27 g of the said product in the form of a liquid boiling at 43-44 C at 20 mm Hg.

EXAMPLE Vlll 4-(7-D1METHYLAM1NOPROPYL)-[4Hl-THIENO- [3,2-b] [fl-BENZAZEPINE STEP A: l0-HYDROXY-9,10-DlHYDRO-[4H]- 40 g of sodium borohydride were added with stirring to a solution of 40 g of l0-oxo-9,l0-dihydro-[4H]- thieno-[3,2-b] [f]-benzazepine in 800 ml of dioxane and 80 ml of water and the mixture was heated at 50 C with stirring for 2 hours. The mixture was cooled to 20 C and then another 20 g of sodium borohydride were added followed by heating with stirring at 50 C for 2 hours. Again, 20 g of sodium borohydride were added thereto and the mixture was stirred for 3 hours at 50 C and then 16 hours at room temperature. The mixture was poured into a ice-water mixture and was then extractedwith ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and distilled to dryness under reduced pressure to obtain 40 g of l0-hydroxy-9,l0-dihydro-[4H1-thieno- [3,2-b] [f] -benzazepine which was used as is for the next step.

STEP B: [4H]-THIENO-[3,2-b] [f]-BENZAZEP1NE 40 g of alumina were added with stirring to a solution of 40 g of the product from Step A in 600 ml of benzene and the mixture was refluxed for 16 hours and then was cooled. The mixture was vacuum filtered and the filter was rinsed with methylene chloride. The filtrate was distilled to dryness in vacuo to obtain 32.6 g of [4H]-thieno-[3,2-b] [f]-benzazepine which was used as is for the next step.

For analysis, the product was purified by crystallization from isopropyl ether to obtain the product in the form of red crystals melting at 187 C with decomposition and soluble in chlorinated organic solvents, alcohols and ether and insoluble in water.

Analysis: C H NS; molecular weight 199.28

Calculated: 7zC 72.35 7rH 4.55 "/rN 7.03 715 16.06 Found: 71.9-71.9 4.9-4.6 7.5-7.0 15.9

1R Spectrum (chloroform):

Presence of NH at 340l" of aromatic and of conjugated C=C U.V. Spectrum (ethanol):

Max. at 238 nm E 3 e 1600 Max. at 270 nm E 6 22.000 lnflex. towards 284 nm E lr 737 lnflex. towards 304 nm E 233 lnflex. towards 390 nm E 3 STEP C: 4-(y-DIMETHYLAM1NOPROPYL) [4H]- TH1ENO-[3,2-b] [f]-BENZAZEPINE 3.6 g of 50% sodium hydride suspended in vaseline oil were added to a solution of 6 g of [4H]-thieno-[3,2- b] [f]-benzazepine in m1 of refluxing xylene and the mixture was refluxed with stirring for 1 hour. 12 m1 of y-dimethylaminopropyl chloride were added thereto and the mixture was refluxed for 2 hours. After cooling, the mixture was poured in an ice-water mixture and was extracted with ether. The organic phase was washed with water and was then extracted with 2N hydrochloric acid. The separated aqueous solution was made alkaline with sodium hydroxide and was then extracted with ether. The ether phase was washed with water, dried over magnesium sulfate and distilled to dryness under reduced pressure. The residue was redissolved in ether and the solution was passed through a column of magnesium silicate. The obtained ether phase was distilled to dryness under reduced pressure to obtain 4.73 g of 4-(y-dimethylaminopropyl)-[4H]- thieno-[3,2-b] [fl-benzazepine which was reacted with fumaric acid to form its fumarate. The product was identical to that of Example 111.

EXAMPLE 1X HYDROCHLORIDE OF 4-(13- METHYLAMlNOETHYL)-9,10-DIHYDRO-[4H1- THIENO-[3,2-b] [fl-BENZAZEPINE Using the procedure of Example V, 9,10-dihydro- [4H]-thieno-[3,2-b] [fl-benzazepine was reacted with B-dimethylaminoethyl chloride to form 4-(B- dimethylaminoethyl)-9,10-dihydro-[4H]-thieno-[3,2- b] [f]-benzazepine which was reacted by the procedure of Example VI with ethyl chloroformate to form 4-(B- N-methyl-N-ethoxycarbonylaminoethyl)-9,IO-dihydro- [4H]-thieno-[3,2-b][f]-benzazepine which was reacted with 2N potassium hydroxide to form 4-(fimethylaminoethyl)-9,l0-dihydro-[4H]-thieno-[3,2-b]

[fl-benzazepine. The latter was reacted with hydroucts. The ptosis provoked by injection of reserpine was diminished by the previous injection of the test compounds so much more the higher the dose. The results are expressed as a percentage of protection as compared with controls not having received reserpine. The results are reported in Table I.

TABLE I Test Product 7: of protection benzazepine (C) chloric acid in ethyl acetate to form the corresponding hydrochloride in the form of a cream solid melting at 248 C and soluble in methanol and water, slightly soluble in isopropanol and insoluble in ether and ethyl acetate.

EXAMPLE X EXAMPLE XI HYDROCHLORIDE OF 4-(B- DIMETHYLAMINOETHYL)-9,10-DIHYDRO-[4H]- THIENO-[3,2-b] [f]-BENZAZEPINE 4-(B-dimethylaminoethyl)-9,l0-dihydro-[4H1- thieno-[3,2-b] [fl-benzazepine of Example IX was reacted with hydrochloric acid in methanol to obtain the corresponding hydrochloride melting at 218 C and occurring in the form of cream solid soluble in methanol and water, slightly soluble in ethyl acetate and isopropanel and insoluble in chloroform.

PHARMACOLOGICAL STUDY A. ANTIDEPRESSIVE ACTIVITY:

The antidepressive activity was determined by antagonism exerted by the compounds against the depressant effect of reserpine which effect is measured by the test of ptosis of the eyelid codified by RUBIN [J. Pharm. Exp. Ther., Vol. 120(1957), p. I251. The said test is used to permit a quantitative evaluation of the state of the animal but the antagonism is exercerised also with all neuro-depressive symptoms of reserpine: immobility, adynamia, myosis and hypothermia.

The readings were taken every hour for 6 hours after the intraperitoneal injection of 1 mg/kg of the resperpine to groups of rats who had received intraperitoneally one hour before varying doses of the test prod- From there results, the dose that reduced 50% of ptosis of the eyelid provoked by reserpine, DA was 2 mg/kg of compound A, 4 mg/kg for compound B and 10 m/kg for compound C.

B. POTENTIALIZATION OF DOPA:

The administration of DOPA [racemic B-(3,4-dihydroxyphenyl)alanine] to mice pretreated with l-isonicotinoyl-2-isopropylhydrazine 18 hours before the test produced a certain number of symptoms: hypertonicity, agitation, crying, aggressiveness, salivation, exophthalmia. The administration of an antidepressant 1 hour before the injection of DOPA potentializes the intensity of the effects.

Male mice weighing between 18 and 22 gm received 50 mg/kg of 1-isonicotinoyl-Z-isopropyl-hydrazine intraperitoneally 18 hours before the test and then received an intraperitoneal injection of the test product in aqueous solution in increasing doses. One hour later, they received an intraperitoneal injection of 50 mg/kg of DOPA and then the different effects were evaluated I5 and 30 minutes after the DOPA injection. Each symptom was evaluated from 0 to 3 for each animal and the different notations were totaled for each dose. The totals obtained are reported in Table II as a percentage of the total obtained by control animals.

TABLE II Dose administered in mg/kg Test compound 2 5 I0 20 A 173 I84 188 B 247 273 269 1 hour later received intraperitoneally 10 mg/kg of tetrabenazine. The animals were tested I,1 /z and 2 hours after the injection of tetrabenazine. Each animal was evaluated for passive ptosis of the eyelid and the catatonic state, and the totalized values obtained for each group of rats in the course of four tests are noted. The results expressed as a percentage of protection are reported in Table III.

TABLE III Dose in of protection Test Compound mg/kg ptosis catatonic B 5 5O 0 10 99 ll C 5 98 l5 l0 l00 The results show that the DA for compound A was 3-4 mg/kg for ptosis and 5 mg/kg for catatonic state, for compound B was 5 mg/kg for ptosis and more than 20 mg/kg for catatonic state and for compound C was 1.5 mg/kg for ptosis and mg/kg for catatonic state. D. POTENTIALIZATION OF SLEEPING TIME The potentialization of sleeping time was determined with a test with amytal (5-ethyl-5-isoamyl-barbituric acid). Groups of female mice weighing between 18-22 g were maintained at 25 C for the duration of the test. The product studied was administered intraperitoneally at different doses 1 hour before the intravenous injection of 80 mg/kg of amytal. The sleeping time during which the reflex of righting of the mouse is negative was noted. The test compounds in aqueous solution of hydrochloric acid of a pH of 3 were administed at the doses of Table IV. For each group, the average sleeping The results of Table IV show that the two products potentialize the sleeping time provoked by amytal. E. ACUTE TOXICITY DETERMINATION:

The acute toxicity was determined on mice of the Swiss strain weighing about 20 g to which the test product was administered intraperitoneally in increasing doses. The animals were then observed for one week. The DL dose was 150 mg/kg for compound A, I80

mg/kg for compound B, I50 mg/kg for compound C and 300 mg/kg for the fumarate of I0-oxo-4-(ydimethylaminopropyl)-9,lO-dihydro-[4H]-thieno-[3,2- b] [fl-benzazepine.

Various modifications of the compositions and methods of the invention may be made without departing from the spirit or scope thereof and it is to be understood that the invention is to be limited only as defined in the appended claims.

We claim:

II. An antidepressant composition comprising an effective amount of a compound selected from the group consisting of 4-(a-alkylaminoalkyl)-[4H]-thieno-[3,2- b] [f]-benzazepine of the formula l fi wherein R and R are selected from the group consisting of hydrogen, halogen, CF lower alkoxy, lower alkylthio, lower alkyl, sulfonamido and diloweralkylamino, R is selected from the group consisting of hydrogen and lower alkyl, A is alkylene of two to five carbon atoms optionally substituted by lower alkyl, B is selected from the group consisting of hydrogen and lower alkyl, C is lower alkyl, Y is selected from the group consisting of hydrogen, hydroxy, lower alkoxy and lower alkanoyloxy, X is hydrogen or taken together with Y forms a carbon-carbon double bond, 2 is selected from the group consisting of hydrogen and lower alkyl and Z is selected from the group consisting of hydrogen, lower alkyl and lower alkoxy or taken with Y forms a member of the group consisting of =0, lower alkylenedioxy, lower alkylenedithio and thioloweralky leneoxy and a non-toxic, pharmaceutically acceptable acid addition salt thereof a pharmaceutical carrier therefor.

2. A method of preventing and/or treating depression in warm-blooded animals comprising administering to a warm-blooded animal an antidepressant effective amount of a compound selected from the group consisting of 4-(a-alkylaminoalkyl)-[4H]-thieno-[3,2-b] [fl-benzazepine of the formula wherein R and R are selected from the group consisting of hydrogen, halogen, CH lower alkoxy, lower alkylthio, lower alkyl, sulfonamino and diloweralkylamino, R is selected from the group consisting of hydrogen and lower alkyl, A is alkylene of two to five carbon atoms optionally substituted by lower alkyl, B is selected from the group consisting of hydrogen and lower alkyl, C is lower alkyl, Y is selected from the group consisting of hydrogen, hydroxy, lower alkoxy and lower alkanoyloxy, X is hydrogen or taken together with Y forms a carbon-carbon double bond, Z is selected from the group consisting of hydrogen and lower alkyl and Z is selected from the group consisting of hydrogen, lower alkyl and lower alkoxy or taken with Y forms a member of the group consisting of =0, lower alkylenedioxy, lower alkylenedithio and thioloweralkyleneoxy and a non-toxic, pharmaceutically acceptable acid addition salt thereof.

3. The method of claim 2 wherein the compound is selected from the group consisting of 4-(ydimethylaminopropyl)-[4H]-thieno-[3,2-b] [f]- benzazepine and the acid fumarate salt.

4. The method of claim 2 wherein the compound is selected from the group consisting of 4-(ymethylaminopropyl)-9,l-dihydro-[4H1-thieno-[3,2- b] [f]-benzazepine and the hydrochloride salt.

5. The method of claim 2 wherein the compound is selected from the group consisting of 4-(ydimethylaminopropyl)-9, l 0-dihydro-[4l-l1-thieno-[3 ,2- b] [f]-benzazepine and the hydrochloride salt.

6. The method of claim 2 wherein the compound is selected from the group consisting of 4-('ydimethylamino-B-methylpropyl)-9,lO-dihydro-[4H1- thieno-[3,2-b] [f]-benzazepine and the hydrochloride salt.

7. The method of claim 2 wherein the compound is selected from the group consisting of 4-(ydimethylaminopropyl l 0-hydroxy-9, l O-dihydro- [4H]-thieno-[3,2-b] [fl-benzazepine and the acid fumarate salt.

8. The method of claim 2 wherein the compound is selected from the group consisting of 4-(ydimethylaminopropyl)-l0-oxo-9,l0-dihydro-[4H]- thieno-[3,2-b] [f]-benzazepine and the acid fumarate salt.

9. The method of claim 2 wherein the compound is selected from the group consisting of 4-(B- methylaminoethyl)-9,l0-dihydro-[4H]-thieno-[3,2-b] [fl-benzazepine and the hydrochloride salt.

10. The method of claim 2 wherein the compound is selected from the group consisting of 4-(B- dimethylaminoethyl)9,l0-dihydro-[4H]-thieno-[3,2- b] [fl-benzazepine and the chlorohydride salt.

11. The method of claim 2 wherein the compound is selected from the group consisting of. 4-(ymethylaminopropyl)-4H]-thieno-[3,2-b] [f]- 

1. AN ANTIDEPRESSANT COMPOSITION COMPRISING AN EFFECTIVE AMOUNT OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 4-(A-ALKYLAMINOALKYL)-(4H)-THIENO-(3,2-B) (F)-BENZAZEPINE OF THE FORMULA
 2. A method of preventing and/or treating depression in warm-blooded animals comprising administering to a warm-blooded animal an antidepressant effective amount of a compound selected from the group consisting of 4-( Alpha -alkylaminoalkyl)-(4H)-thieno-(3,2-b) (f)-benzazepine of the formula
 3. The method of claim 2 wherein the compound is selected from the group consisting of 4-( gamma -dimethylaminopropyl)-(4H)-thieno-(3,2-b) (f)-benzazepine and the acid fumarate salt.
 4. The method of claim 2 wherein the compound is selected from the group consisting of 4-( gamma -methylaminopropyl)-9,10-dihydro-(4H)-thieno-(3,2-b) (f)-benzazepine and the hydrochloride salt.
 5. The method of claim 2 wherein the compound is selected from the group consisting of 4-( gamma -dimethylaminopropyl)-9,10-dihydro-(4H)-thieno-(3,2-b) (f)-benzazepine and the hydrochloride salt.
 6. The method of claim 2 wherein the compound is selected from the group consisting of 4-( gamma -dimethylamino- Beta -methylpropyl)-9,10-dihydro-(4H)-thieno-(3,2-b) (f)-benzazepine and the hydrochloride salt.
 7. The method of claim 2 wherein the compound is selected from the group consisting of 4-( gamma -dimethylaminopropyl)-10-hyDroxy-9,10-dihydro-(4H)-thieno-(3,2-b) (f)-benzazepine and the acid fumarate salt.
 8. The method of claim 2 wherein the compound is selected from the group consisting of 4-( gamma -dimethylaminopropyl)-10-oxo-9, 10-dihydro-(4H)-thieno-(3,2-b) (f)-benzazepine and the acid fumarate salt.
 9. The method of claim 2 wherein the compound is selected from the group consisting of 4-( Beta -methylaminoethyl)-9,10-dihydro-(4H)-thieno-(3,2-b) (f)-benzazepine and the hydrochloride salt.
 10. The method of claim 2 wherein the compound is selected from the group consisting of 4-( Beta -dimethylaminoethyl)-9,10-dihydro-(4H)-thieno-(3,2-b) (f)-benzazepine and the chlorohydride salt.
 11. The method of claim 2 wherein the compound is selected from the group consisting of 4-( gamma -methylaminopropyl)-(4H)-thieno-(3,2-b) (f)-benzazepine and the maleate salt. 